Modulators of programmed death-ligand-1 and/or programmed death-ligand-2

Abstract

The present disclosure is concerned with dipeptide compounds for the treatment of various cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
       1. A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein n is 0 or 1; 
         wherein each of R 1a  and R 1b , when present, is independently selected from hydrogen, halogen, and unsubstituted C1-C4 alkyl; 
         or wherein each of R 1a  and R 1b , when present, are covalently bonded and, together with the intermediate atoms, comprise an unsubstituted cyclopropyl group; 
         wherein each of R 2  and R 4  is independently selected from hydrogen and unsubstituted C1-C4 alkyl; 
         wherein R 3  is selected from —(C1-C8 alkyl)NR 10a R 10b , —(C1-C8 alkyl)C(O)NR 10a R 10b , unsubstituted C2-C8 alkyl, and —(C1-C4)Ar 2 ;
 wherein each of R 10a  and R 10b  is independently selected from hydrogen and unsubstituted C1-C4 alkyl; 
 wherein Ar 2  is C6 aryl para-substituted with a —(CH 2 ) m NR 20a R 20b  group, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
 wherein m is 1, 2, 3, or 4; and 
 wherein each of R 20a  and R 20b  is independently selected from hydrogen and unsubstituted C1-C4 alkyl; 
 
 
         wherein each of R 5a  and R 5b  is hydrogen; 
         or wherein each of R 5a  and R 5b  is independently unsubstituted C1-C4 alkyl; 
         or wherein each of R 5a  and R 5b  are covalently bonded and, together with the intermediate atom, comprise an unsubstituted C3-C6 group; and 
         wherein R 6  is hydrogen; 
         or wherein each of R 5a  and R 5b  together are covalently bonded to R 6  and, together with the intermediate atom, comprise a C3-C5 heteroaryl group substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and 
         wherein Ar 1  is selected from C6 aryl, indolyl, pyridinyl, benzo[d]oxazole, and benzo[d]thiazole, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, 
         or a pharmaceutically acceptable salt thereof, 
         provided that when each of R 5a  and R 5b  is hydrogen, then R 3  is not unsubstituted C2-C8 alkyl, 
         provided that when n is 0, then each of R 5a  and R 5b  is independently unsubstituted C1-C4 alkyl or each of R 5a  and R 5b  are covalently bonded and, together with the intermediate atom, comprise an unsubstituted C3-C6 group, and R 6  is hydrogen, and 
         provided that the compound is not: 
       
       
         
           
           
               
               
           
         
       
     
     
       2. The compound of  claim 1 , wherein n is 0. 
     
     
       3. The compound of  claim 1 , wherein n is 1. 
     
     
       4. The compound of  claim 1 , wherein each of R 1a  and R 1b , when present, is hydrogen, or wherein each of R 1a  and R 1b , when present, are covalently bonded and, together with the intermediate atom, comprise an unsubstituted cyclopropyl group. 
     
     
       5. The compound of  claim 1 , wherein each of R 2  and R 4  is hydrogen. 
     
     
       6. The compound of  claim 1 , wherein R 3  is —(C1-C8 alkyl)NR 10a R 10b . 
     
     
       7. The compound of  claim 1 , wherein R 3  is unsubstituted C2-C8 alkyl. 
     
     
       8. The compound of  claim 1 , wherein R 3  is —(C1-C4)Ar 2 . 
     
     
       9. The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       10. The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       11. The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       12. The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       13. The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 21a , R 21b , R 21c , R 21d , and R 21e  are independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R 21a , R 21b , R 21c , R 21d , and R 21e  are hydrogen. 
       
     
     
       14. The compound of  claim 1 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       15. A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       16. A pharmaceutical composition comprising an effective amount of the compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
       17. A pharmaceutical composition comprising an effective amount of the compound of  claim 15 , and a pharmaceutically acceptable carrier.